Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4 + T cells partly via transforming growth factor-β1

Clin Exp Immunol. 2017 Jan;187(1):113-123. doi: 10.1111/cei.12870. Epub 2016 Nov 2.

Abstract

Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4+ T cells. Lack of interleukin (IL)-12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-β1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-β1 signalling we demonstrate that tolDC regulate CD4+ T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF-βRII on CD4+ T cells from RA patients and healthy controls, RA patient CD4+ T cells are measurably less responsive to TGF-β1 than healthy control CD4+ T cells [reduced TGF-β-induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-γ secretion]. However, CD4+ T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-β1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.

Keywords: TGF-β1; regulation; rheumatoid arthritis; tolerogenic dendritic cells.

MeSH terms

  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / therapy*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Cholecalciferol / pharmacology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / transplantation
  • Dexamethasone / pharmacology
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Immune Tolerance*
  • Immunomodulation
  • Immunotherapy / methods*
  • Interleukin-12 / genetics
  • Interleukin-12 / metabolism
  • Lymphocyte Activation
  • Smad2 Protein / metabolism
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta1
  • Interleukin-12
  • Cholecalciferol
  • Dexamethasone